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Echinocandins Comparison Essay

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Echinocandins comparison essay

Echinocandin

Echinocandins are antifungal drug s that inhibit the synthesis of glucan in the cell wall. probably via noncompetetive inhibition of the enzyme 1,3-β glucan synthase cite journal |author=Morris MI, Villmann M |title=Echinocandins in the management of invasive fungal infections, part 1 |journal=Am J Health Syst Pharm |volume=63 |issue=18 |pages=1693–703 |year=2006 |month=September |pmid=16960253 |doi=10.2146/ajhp050464.p1 |url=http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16960253 ] cite journal |author=Morris MI, Villmann M |title=Echinocandins in the management of invasive fungal infections, Part 2 |journal=Am J Health Syst Pharm |volume=63 |issue=19 |pages=1813–20 |year=2006 |month=October |pmid=16990627 |doi=10.2146/ajhp050464.p2 |url=http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16990627 ] and are thus called penicillin of antifungals (a property shared with papulacandins. see history below).

It is used in candidiasis and aspergillosis. cite journal |author=Wagner C, Graninger W, Presterl E, Joukhadar C |title=The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications |journal=Pharmacology |volume=78 |issue=4 |pages=161–77 |year=2006 |pmid=17047411 |doi=10.1159/000096348 |url=http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=PHA2006078004161 ]

They are fungicidal against yeast eg most species of " Candida " (but not against " Cryptococcus ", " Trichosporon " & " Rhodotorula ") and fungistatic against mold eg " Aspergillus " (but not " Fusarium " & " Rhizopus ") modest or minimally active active against dimorphic fungi eg " Blastomyces " and " Histoplasma ". These have some activity against the spores of the fungus " Pneumocystis carinii ".

The present day clinically used echinocandins are semisynthetic pneumocandins which are chemically lipo-peptide in nature, consisting of large cyclic (hexa)peptides linked to a long chain fatty acid. Discovery of echinocandins stemmed from studies on papulacandin s isolated from a strain of Papularia sphaerosperma (Pers.), which were lipo-saccharide ie fatty acid derivatives of a disaccharide which also blocked the same target 1,3-β glucan synthase and had only anti-candida action (narrow spectrum). Screening of natural products of fungal fermentation in 1970's lead to the discovery to Echinocandins new group of antifungals with broad range activity against Candida species. One of the first Echinocandins of the pneumocandin type, discovered in 1974, Echynocandin B could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to Cilofungin. first echinofungin analog that entered clinical trials in 1980, which was later withdrawn for a toxicity presumably due to the solvent system needed for systemic administration. The semisysnthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity but low toxicity. The first approved of these newer echinocandins was Caspofungin and later Micafungin and Anidulafungin were also approved. All these preparations so far have low oral bioavailability and thus must be given intravenous only. Echinocandins have now become one of the first line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

Advantages of echinocandins:

* broad range (especially against all candida ), thus can be given empirically in febrile neutropenia & stem cell transplant
* Can be used in case of azole resistant candida or use as a second line agent for refractory aspergillosis
* long half life (polyphasic elimination: alpha phase 1-2 hours + beta phase 9-11 hours + gamma phase 40-50 hours)
* low toxicity. only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely allergy and anaphylaxis
* not an inhibitor, inducer, or substrate of the cytochrome P450 system, or P-glycoprotein, thus minimal drug interactions
* lack of interference from renal failure and hemodialysis.
* no dose adjustment is necessary based on age, gender, race
* better (or no less effective) than Amphotericin B and fluconazole against yeast infections

Disadvantages of echinocandins:
* Embryotoxic cite web |url=http://www.clevelandclinicmeded.com/medicalpubs/pharmacy/mayjune2003/antifungal.htm |title=Pharmacotherapy Update - New Antifungal Agents: Additions to the Existing Armamentarium (Part 1) |format= |work= |accessdate= ] (category C) thus cannot be used in pregnancy
* Needs dose adjustment in liver disease

Capsofungin has some interference with cyclosporin metabolism and micafungin has some interference with sirolimus (rapamycin), but anidulafungin needs no dose adjustments when given with cyclosporin. tacrolimus or voriconazole [Harroison's Principle of Internal Medicine ].

List of echinocandins:
* pneumocandin s (cyclic hexa-peptides linked to a long chain fatty acid):
** Echinocandin B not clinically used for risk of hemolysis
** Cilofungin (withdrawn from trials due to solvent toxicity)
** Caspofungin (Cancidas®)
** Micafungin (FK463)
** Anidulafungin (VER-002, V-echinocandin, LY303366)

* papulacandin s (fatty acid derivatives of a disaccharide)
** papulacandin B

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Other articles

Study on the comparative activity of echinocandins on murine gut colonization by Candida albicans

Colonization of the gastrointestinal (GI) tract by Candida species is a principal pathogenetic event for development of invasive candidiasis. Importantly, the effect of echinocandins, the preferred antifungal agents for treatment of invasive candidiasis, on GI tract colonization by Candida spp. is currently unknown. Herein, we used an established model of persistent murine GI tract colonization by Candida albicans to test the ability of different echinocandins to eradicate the yeast from murine gut. Adult male Crl:CD1 (ICR) BR mice were fed with chow containing C. albicans and subsequently treated with different echinocandins or normal saline via daily intraperitoneal injections for 10 days. Quantitative stool cultures were performed immediately before (week one), and weekly for three months after discontinuation of treatment. Notably, treatment with all three echinocandins used (caspofungin, anidulafungin, and micafungin) resulted in eradication of Candida albicans from the stools, as evidenced by the significant reduction of yeast cells from a mean of 4.2 log10 CFU/g of stool before treatment (week one of colonization) to undetectable (<2 log10 CFU/g of stool) levels (week 12, P < 0.0001). In contrast, there was no significant reduction of Candida yeast cells in the stools of control mice. Collectively, the ability of echinocandins to eradicate C. albicans from the stools could have important implications in prophylaxis of high-risk patients for development of invasive candidiasis originating from the GI tract.

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Unbound MEDLINE: Echinocandin antifungal drugs in fungal infections: a compariso

Echinocandin antifungal drugs in fungal infections: a comparison. Abstract

This review compares the pharmacology, spectrum of antifungal activity, pharmacokinetic and pharmacodynamic properties, safety and clinical efficacy of the three licensed echinocandins: caspofungin, micafungin and anidulafungin. Echinocandins inhibit the synthesis of 1,3-β-D-glucan, an essential component of the fungal cell wall, and represent a valuable treatment option for fungal infections. The echinocandins exhibit potent in vitro and in vivo fungicidal activity against Candida species, including azole-resistant pathogens. For all agents, strains with drug minimum inhibitory concentrations (MICs) of ≤ 2 μg/mL are considered susceptible; the MIC at which 90% of isolates tested were inhibited (MIC₉₀) values are typically <2 μg/mL but 100-fold higher MIC₉₀ values are seen with Candida parapsilosis (1-2 μg/mL) and Candida guilliermondii (1-4 μg/mL). Activity is comparable between the three agents, although limited data indicate that anidulafungin may have low MICs against C. parapsilosis and Candida glabrata strains that demonstrate elevated MICs to caspofungin and micafungin. All three drugs have good fungistatic activity against Aspergillus spp. although minimal effective concentrations of micafungin and anidulfungin are 2- to 10-fold lower than those for caspofungin. Synergistic/additive in vitro effects of echinocandins when combined with a polyene or azole have been observed. Clinical resistance to the echinocandins is rare despite case reports of caspofungin resistance in several Candida spp. Resistance has been attributed to mutations in the FKS1 gene within two hot spot regions, leading to amino acid substitutions, mostly at position 645 (serine), yet not all FKS1 mutants have caspofungin MICs of >2 μg/mL. Of the three echinocandins, the in vitro 'paradoxical effect' (increased growth at supra-MIC drug concentrations) is observed least often with anidulafungin. All echinocandins have low oral bioavailability, and distribute well into tissues, but poorly into the CNS and eye. Anidulafungin is unique in that it undergoes elimination by chemical degradation in bile rather than via hepatic metabolism, has a lower maximum concentration and smaller steady state under the concentration-time curve but longer half-life than caspofungin or micafungin. In children, dosing should be based on body surface area. Daily doses of caspofungin (but not micafungin and anidulafungin) should be decreased (from 50 to 35 mg) in moderate liver insufficiency. All echinocandins display concentration-dependent fungicidal (for Candida) or fungistatic (for Aspergillus) activity. The postantifungal effect is 0.9-20 hours against Candida and <0.5 hours against Aspergillus. The echinocandins are well tolerated with few serious drug-drug interactions since they are not appreciable substrates, inhibitors or inducers of the cytochrome P450 or P-glycoprotein systems. In parallel with the greater clinical experience with caspofungin, this agent has a slightly higher potential for adverse effects/drug-drug interactions, with the least potential observed for anidulafungin. Caspofungin (but not micafungin or anidulafungin) dosing should be increased if coadministered with rifampicin and there are modest interactions of caspofungin with calcineurin inhibitors. All three agents are approved for the treatment of oesophageal candidiasis, candidaemia and other select forms of invasive candidiasis. Only micafungin is licensed for antifungal prophylaxis in stem cell transplantation, whereas caspofungin is approved for empirical therapy of febrile neutropenia. Caspofungin has been evaluated in the salvage and primary therapy of invasive aspergillosis. Combination regimens incorporating an echinocandin showing promise in the treatment of aspergillosis. However, echinocandins remain expensive to use.

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Drugs 71:1 2011 Jan 1 pg 11-41

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Eukaryotic Organisms - Free Science Essay - Essay UK

Free Science essays Eukaryotic Organisms

Fungi are eukaryotic organisms which are found everywhere on the earth in every environmental conditions including temperate to tropical areas. There are about two million kinds of living organisms on the earth, of which fungi constitute about a hundred thousand species and many more await discovery. Of those described, nearly 150 species are generally recognized as primary pathogens of man and animals. They may cause a variety of infections, ranging from systemic and potentially fatal diseases to localized cutaneous, subcutaneous or mucosal infections and the fungi causing these infections are termed as opportunistic pathogens. The most common fungi those act as causal agents are the species of Aspergillus and Candida. Candida species are frequently found in the normal microbiota of humans, which facilitates their encounter with surfaces of immunocompromised host and most implanted biomaterials.
The majority of microorganisms in their natural habitats grow as structured biofilm communities attached to the surfaces rather than individually in suspension. It is known that about 65% of all human microbial infections involve biofilms (Potera 1999). In biofilms, cells are encapsulated within a matrix of protective extracellular material and display altered character in comparison to planktonic counterpart. The biofilms are significantly less susceptible to antimicrobial agents and display unique characteristics that confer survival advantages against host immunity (O'Toole et al. 2000; Mah et al. 2001 Ramage et al. 2006).
Candida albicans is also a fungal species that remains most commonly associated with biofilm formation (Douglas, 2002; Douglas, 2003; Kumamoto, 2002), and the increase in Candida infections in the last decade has increased proportionately to the widespread use of a broad range of medical implant devices, mainly in persons with immunosuppresed host defenses. Strikingly, fungi (mainly C. albicans) are the third leading cause of catheter-related infections, representing the second highest colonization-to-infection rate and the overall highest crude mortality (Crump et al. 2000). The formation of Candida biofilms carries important clinical repercussions because of their increased resistance to antifungal therapy and the ability of cells within biofilms to withstand host immune defenses. Also, biofilm formation on medical devices can have a negative impact on the host by causing failure of the device and by serving as a reservoir or source for future continuing infections (Douglas, 2002; Kojic et al. 2004). Antifungal therapy alone is insufficient for cure and the affected devices generally need to be removed (Mermel et al. 2001; Rex et al. 2000). Removal of these devices has serious implications in the setting of heart valves, joint prostheses, and central nervous system shunts. Until recently, the reason for the need for device removal has been a mystery.

C. albicans has also evolved various mechanisms to counter the front line antifungal drugs available for the treatment of candidiasis. Relatively few classes of antifungal drugs are available in the market and the development of resistance enlarges the problem. The antifungal drugs that are in clinical use or under advance stages of clinical evaluation are polyenes (amphotericin B, nystatin), azoles (clotrimazole, ketoconazole, fluconazole, itraconazole, voriconazole, posaconazole, oxiconazole and ravuconazole), 5-flucytosine, allylamines (terbinafine), echinocandins (caspofungin, anidulafungin, FK463) (Carrillo-Munoz et al. 2006). Perhaps resistance to polyenes is a rare phenomenon, but drugs of this class can impose significant side effects.
Candida albicans has been reported to be responsible for the release of arachidonic acid (AA) from the host cells during infections (Castro et al. 1994, Deva et al. 2000) which may modulate the cell growth, morphogenesis and invasiveness of causal agent by several modes. AA is a precursor for the production of eicosanoids which play an important role in morphogenesis and biofilm formation. Prostaglandin E2 (PGE2) is a primary product of arachidonic acid metabolism in most of the eukaryotic cells that has also been reported in pathogenic fungi as well (Lamacka et al. 1995, Lodewyk et al. 1997). Enhanced prostaglandin production during fungal infections could be one of the important factors in promoting colonization as well as chronic infections. The shift in host immune response towards increased colonization and chronic infections is due to PGE2 which has ability to elicit both pro and anti inflammatory responses depending upon the host cells (Mairi et al. 2001; Mairi et al. 2002). Exogenous AA has been reported to increase PGE2 level significantly in C. albicans whereas the behavior of Candida non-albicans species and resistant strains in presence of AA is not much studied till now (Mairi et al. 2001; Mairi et al. 2002; Mohammed et al. 2005). The studies related to determining level of PGE2 in C. albicans and non-albicans species in presence of AA may help in understanding the biofilm forming capacity.
The content of biofilms and the properties such as reduced susceptibility to antimicrobial agents make them difficult to remove and, in the case of biofilms associated with disease, a therapeutic dilemma. The cell surface is also the site that mediates adherence with itself, other microbes in biofilms and host surfaces, binds host ligands and interacts with innate and acquired host defenses. The cell wall structure of C. albicans biofilm, its proteins, and their role has proven a key factor of the relationship of C. albicans and the host (Costerton et al. 1999). Generally cell wall of C. albicans consists of polysaccharides meshwork, primarily. - 1, 3-glucan, and. -1, 6-glucan with the some chitin. C. albicans cell wall has two major classes of proteins (CWPs) based on whether they are covalently attached to glucan. The most abundant attached proteins are linked to. - 1, 6-glucan through a glycophosphatidylinositol (GPI) remnant (GPI-CWP), whereas the least abundant are attached via an alkali labile linkage. The nonglucan-attached proteins may belong to one of the two classes with the one class having the signal for conventional secretion whereas the most abundant class lacks this signal (Costerton et al. 1999; Jenkinson et al. 2002; Douglas, 2003). Several studies have focused on identifying the cell wall proteome including both covalent and non-covalent attached proteins (Douglas 2003, Kumamoto, 2002). The cell wall of this dimorphic organism is a robust but dynamic structure that protects organisms from environmental insults and adjusts in response to the environment (Chaffin, 2008). The cell surface is also the site that mediates adherence with itself, other microbes in biofilms and host surfaces, bind host ligands and interact with innate and acquired host defenses. The study of cell wall structure, its proteins, and their functions has proven a key for approaching the relationship of C. albicans and the host in health and disease (Chaffin, 2008).
There are other proteins that are not covalently attached and found at the cell surface (Nombela et al. 2006). Several studies have employed proteomic approaches to identify proteins of the cell wall sub proteome for both covalent and non-covalent protein species (Pitarch et al. 2006; Saville et al. 2006; Urban et al. 2003). Candida biofilm formation is the major threat for immunocompromised patient as well as patient with medical implants. The important issue is the diagnosis of systemic infection of Candida particularly in patients who are under medical treatment of transplantation. Rapid diagnosis of fungi may be helpful in reducing the use of inappropriate antifungal compounds to treat Candida spp. that are resistant to a particular agent (Ghannoum et al.,1999). Diagnosis of invasive Candida infections may be difficult due to the variability and lack of specificity of clinical presentations and also the symptoms (eg. fever) of Candida infections are not very specific (Larriba et al. 2000). A definitive diagnosis is not reached until late in the infection, with subsequent delays in the initiation of therapy that may result in substantial morbidity and mortality (Hernando et al. 2006). Laboratory diagnosis of Candida infections includes microscopic examination of smear from cutaneous, mucosal, oesophageal and vaginal lesions, culture of sputum, bronchoalveolar lavage, oesophageal brushings, urine, stool and surgical drains. These methods are time consuming, tedious and are not fool proof. Biopsy may be required in some cases of deep-seated candidiasis. Novel methods of diagnosis include PCR based amplification of the infectious agents DNA. This method is sensitive, rapid and less cumbersome but is limited due to false positive results arising from the non-specific contamination with other microorganisms sharing the same ecological niche and also the technique is not available commercially (Bille, 2005). Antibody based detection techniques for immuno-diagnosis of systemic candidiasis include latex agglutination (Dee et al. 1981), counter immuno-electrophoresis. indirect immuno-fluorescence and enzyme linked immunoassay (Kostiala & Kostiala, 1981, Quindos et al. 1987). The antibody-based approaches for diagnosis of Candida infections are rapid and sensitive but often the sensitivity decreases considerably when it comes to discriminating between superficial and disseminated candidiasis (Martinez et al. 1998). This is because of the poly-specific nature of the serum antibodies that sometimes may also lead to false positive results. Thus there is an urgent need to develop new techniques for rapid and accurate diagnosis of these infections.
Monoclonal antibodies (MAbs) are antibody molecules produced by the cells resulting from a single clone and thus are specific to a single epitope of a protein. Diagnostic techniques based on MAbs are rapid, sensitive and very specific (Marcilla et al. 1999). The technique can be pathogen specific, species specific and even stage specific for the same pathogen. Identification of stage specific molecules and development of monoclonal antibodies against them is a promising method of diagnosis (Marot-Leblond et al.,2000). Many protein molecules are constitutively expressed by C. albicans biofilm. These molecules are attractive targets for diagnosis as they are expressed at all times particularly during adherence or biofilm formation and thus offer a reliable diagnostic method decreasing the percentage of false positive results (Fradin et al. 2003). Many monoclonal antibodies have been produced against C. albicans that have therapeutic value (Han et al. 1998 & 2000) but against biofilm cell surface adhesive proteins is rare. Thus identification of new target molecules that are stage specific or constitutively expressed can open new avenues for the development of diagnostic as well as therapeutic monoclonal antibodies against the C. albicans biofilm. Also many molecules identified may be targeted for the development of new antifungal compounds.

There are many proteins that are either cell associated or secreted depending on growth condition. Many enzymes on the other hand are present on the cell surface and cell wall of Candida biofilm (Pugh & Cawson,1975). Biofilm formation on SE disks/ polystyrene cell culture plates are offered a novel approach to study cell surface as well as cell wall proteins that are responsible for adhesion during biofilm formation and also in virulence factor (Pardo et al. 1999). Several workers utilized biofilm to study the cell wall and secretory proteins of C. albicans and there are well-established proteome maps available for yeast form (Rico et al. 1997; Kapteyn et al. 1995).
The objective of the thesis work was to generate monoclonal antibodies against cell surface/cell wall proteins of C. albicans biofilm and to evaluate their therapeutic and/or diagnostic value for Candida infection in the form of biofilm. A total of six strains of Candida albicans were used in the present study to evaluate their biofilm formation. In this piece of work, biofilm formation of different Candida species was compared under different growth conditions supplemented with arachidonic acid and subinhibitory concentration of two antifungals. Along with this study, effect of arachidonic acid and subinhibitory concentration of two antifungals was also evaluated on Candida biofilm and prostaglandin production. Cell surface/ cell wall proteins of C. albicans biofilm were isolated to generation of poyclonal and monoclonal antibodies. The cell surface proteins of C. albicans biofilm were characterized by peptide mass fingerprinting using MALDI-TOF-MS technique. As C. albicans biofilm cell surface/cell wall proteins consist of largest fraction in adhesive proteins, C. albicans biofilm cell surface/cell wall proteins were used for generation and evaluation of monoclonal antibodies for their therapeutic and diagnostic potential. Paratope derived peptides were designed from the sequences obtained by reverse transcription and cDNA sequencing of hybridoma line showing the most effective response.

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Echinocandin - The Full Wiki

Echinocandin: Wikis Uses History

The present day clinically used echinocandins are semisynthetic pneumocandins which are chemically lipo-peptide in nature, consisting of large cyclic (hexa)peptides linked to a long chain fatty acid. Discovery of echinocandins stemmed from studies on papulacandins isolated from a strain of Papularia sphaerosperma (Pers.), which were lipo-saccharide ie fatty acid derivatives of a disaccharide which also blocked the same target 1,3-β glucan synthase and had only anti-candida action (narrow spectrum). Screening of natural products of fungal fermentation in 1970's lead to the discovery to Echinocandins new group of antifungals with broad range activity against Candida species. One of the first Echinocandins of the pneumocandin type, discovered in 1974, Echynocandin B could not be used clinically due to risk of high degree of hemolysis. Screening semisynthetic analogs of the echinocandins gave rise to Cilofungin. first echinofungin analog that entered clinical trials in 1980, which was later withdrawn for a toxicity presumably due to the solvent system needed for systemic administration. The semisysnthetic pneumocandin analogs of echinocandins were later found to have the same kind of antifungal activity but low toxicity. The first approved of these newer echinocandins was Caspofungin and later Micafungin and Anidulafungin were also approved. All these preparations so far have low oral bioavailability and thus must be given intravenous only. Echinocandins have now become one of the first line treatments for Candida before the species are identified, and even as antifungal prophylaxis in hematopoietic stem cell transplant patients.

Advantages

Advantages of echinocandins:

  • broad range (especially against all candida ), thus can be given empirically in febrile neutropenia & stem cell transplant
  • Can be used in case of azole resistant candida or use as a second line agent for refractory aspergillosis
  • long half life (polyphasic elimination: alpha phase 1–2 hours + beta phase 9–11 hours + gamma phase 40–50 hours)
  • low toxicity. only histamine release (3%), fever (2.9%), nausea and vomiting (2.9%), and phlebitis at the injection site (2.9%), very rarely allergy and anaphylaxis
  • not an inhibitor, inducer, or substrate of the cytochrome P450 system, or P-glycoprotein, thus minimal drug interactions
  • lack of interference from renal failure and hemodialysis.
  • no dose adjustment is necessary based on age, gender, race
  • better (or no less effective) than Amphotericin B and fluconazole against yeast infections
Disadvantages

Disadvantages of echinocandins:

  • Embryotoxic [ 4 ] (category C) thus cannot be used in pregnancy
  • Needs dose adjustment in liver disease
Interference

Caspofungin has some interference with ciclosporin metabolism and micafungin has some interference with sirolimus (rapamycin), but anidulafungin needs no dose adjustments when given with ciclosporin, tacrolimus or voriconazole [ 5 ] .

Examples

These criteria have been used in studies and case reports of echinocandin use in the treatment of invasive mold disease and must be considered when evaluating therapeutic outcomes of antifungal therapy.

These criteria of proven, probable, or possible invasive fungal infection can also help pharmacists to evaluate the appropriate use of echinocandin therapy in the absence of culture data or other definitive diagnostic information.


http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16990627 ">Echinocandins in the management of invasive fungal infections, Part 2 - Echinocandins in the management of invasive fungal infections, part 2 -- Morris and Villmann 63 (19): 1813 -- American Journal of Health-System Pharmacy

http://www.ajhp.org/cgi/pmidlookup?view=long&pmid=16960253 ">Echinocandins in the management of invasive fungal infections, part 1 - Am J Health-Syst Pharm -- Sign In Page

Caspofungin, micafungin and anidulafungin are three drugs of the echinocandin class of antifungals available for intravenous treatment of invasive candidiasis and aspergillosis.

In various clinical studies investigating candidemia and invasive candidiasis, Candida esophagitis, and fever in neutropenia, the clinical efficacy of the echinocandin tested was similar to that of established antifungals.


http://content.karger.com/produktedb/produkte.asp?typ=fulltext&file=PHA2006078004161 ">The echinocandins: comparison of their pharmacokinetics, pharmacodynamics and clinical applications - The Echinocandins: Comparison of Their Pharmacokinetics, Pharmacodynamics and Clinical Applications

A comparative evaluation of properties and clinical efficacy of the echinocandins

A comparative evaluation of properties and clinical efficacy of the echinocandins.

Author(s): Kim R, Khachikian D, Reboli AC

Affiliation(s): Cooper University Hospital/UMDNJ-Robert Wood Johnson Medical School Education and Research Building, Division of Infectious Diseases, Department of Medicine, Camden, NJ 08103, USA. kim-rose@cooperhealth.edu

Publication date & source: 2007-07, Expert Opin Pharmacother. 8(10):1479-92.

Publication type: Research Support, Non-U.S. Gov't; Review

With the increase in prevalence of fungal infections, newer antifungal agents are needed to effectively treat invasive disease, and at the same time minimize adverse effects from therapy. The echinocandins comprise a novel class of antifungals; their mechanism of action involves inhibiting 1,3-beta-D-glucan synthase, which is essential in cell wall synthesis for certain fungi. All three echinocandins are US FDA-approved for the treatment of esophageal candidiasis. Caspofungin and anidulafungin are licensed for the treatment of candidemia, and other select forms of invasive candidiasis. Micafungin is at present the only echinocandin approved for prophylaxis of fungal infections in hematopoietic stem cell transplants; whereas caspofungin is approved for empiric therapy of febrile neutropenia. Although all three echinocandins are active against Aspergillus, only caspofungin is presently approved for salvage therapy in invasive aspergillosis. Combination therapy with echinocandins plus other licensed antifungal therapy shows promise in treating invasive aspergillosis. This article will explore the similarities and differences among the echinocandins.

Page last updated: 2007-10-18

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Comparative Efficacy of Echinocandins and Nonechinocandins for the Treatment of Candida parapsilosisInfections: AMeta-analysis - Kale-Pradhan - 2012 -

Comparative Efficacy of Echinocandins and Nonechinocandins for the Treatment of Candida parapsilosis Infections: AMeta-analysis How to Cite

Kale-Pradhan, P. B. Morgan, G. Wilhelm, S. M. and Johnson, L. B. (2010), Comparative Efficacy of Echinocandins and Nonechinocandins for the Treatment of Candida parapsilosis Infections: AMeta-analysis. Pharmacotherapy, 30: 1207–1213. doi: 10.1592/phco.30.12.1207

Author Information

Department of Pharmacy Practice, Eugene Applebaum College of Pharmacy and Health Science, Detroit, Michigan

School of Medicine, Wayne State University, Detroit, Michigan

Department of Pharmacy, Detroit, Michigan

Division of Infectious Diseases, St. John Hospital and Medical Center, Detroit, Michigan

Harper University Hospital, Detroit, Michigan.

* visit http:www.atypon-link.comPPIloiphco. Department of Pharmacy, St. John Hospital and Medical Center, 22101 Moross Road, Detroit, MI 48236;; e-mail: pkale@wayne.edu .

Publication History
  1. Issue online: 6 JAN 2012
  2. Version of Record online: 6 JAN 2012
  3. Manuscript received February 11, 2010. Accepted for publication in final form June 8, 2010…

Study Objective. To compare the efficacy of echinocandins and nonechinocandins in the treatment of candidemia or invasive candidiasis due to Candida parapsilosis .

Design. Meta-analysis of five randomized, blinded, comparative trials.

Patients. A total of 1169 patients (mean age 55.5 yrs, 57.8% male) with invasive candidiasis or candidemia treated with an echinocandin or other antifungal agents.

Measurements and Main Results. The PubMed, MEDLINE, Toxnet, and Cochrane Central Register of Controlled Trials databases were searched for relevant English-language articles to identify appropriate randomized trials. The quality of studies was assessed with the Jadad scoring system. Data on number of patients, age, and treatment success rate were extracted by two investigators independently into a standardized data collection form. Overall C. parapsilosis treatment success rates with echinocandins were compared with nonechinocandins. Jadad scores of the five studies that met all of the selection criteria ranged from 2–5 (out of 5), with a median of 4. Among the 1169 patients with invasive candidiasis or candidemia, 202 (17.3%) had C. parapsilosis. Among these C. parapsilosis cases, 102 received an echinocandin and 100 received a comparator drug. The success rates of treating C. parapsilosis were similar for the echinocandin group versus other antifungal treatment groups (76.5% [78/102] vs 73% [73/100]). A fixed-effects model was applied secondary to a low level of heterogeneity among the studies (I 2 =0%). The combined risk ratio demonstrated that echinocandins are not significantly different from other antifungal agents for the treatment of candidemia or invasive candidiasis due to C. parapsilosis (risk ratio 1.03, 95% confidence interval 0.88–1.21).

Conclusion. Echinocandins are as effective as comparator drugs for the treatment of candidemia or invasive candidiasis due to C. parapsilosis .

Comparison of the in vitro activity of echinocandins against Candida albicans, Candida dubliniensis, and Candida africana by time–kill curves

Comparison of the in vitro activity of echinocandins against Candida albicans. Candida dubliniensis. and Candida africana by time–kill curves

Echinocandins activity against Candida albicans complex species was compared by time–kill methodology.

Differences in killing activity were observed among species and echinocandins.

Anidulafungin was the most active against Candida albicans. Candida dubliniensis. and Candida africana .

Candida albicans was the most susceptible species.

Echinocandins showed no lethality against Candida africana .

Abstract

Candida albicans remains the most common fungal pathogen. This species is closely related to 2 phenotypically similar cryptic species, Candida dubliniensis and Candida africana. This study aims to compare the antifungal activities of echinocandins against 7 C. albicans. 5 C. dubliniensis. and 2 C. africana strains by time–kill methodology. MIC values were similar for the 3 species; however, differences in killing activity were observed among species, isolates, and echinocandins. Echinocandins produced weak killing activity against the 3 species. In all drugs, the fungicidal endpoint (99.9% mortality) was reached at ≤31 h with ≥0.5 μg/mL for anidulafungin in 4 C. albicans and 1 C. dubliniensis. for caspofungin in 1 C. albicans and 2 C. dubliniensis. and for micafungin in 4 C. albicans and 1 C. dubliniensis. None of echinocandins showed lethality against C. africana. Identification of these new cryptic species and time–kill studies would be recommendable when echinocandin treatment fails.

Keywords

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